ES2598083T3 - FGF receptor agonist dimeric compounds (FGFR), procedure for their preparation and therapeutic use thereof - Google Patents

Abstract

Agonist compounds of FGF receptors corresponding to the general formula: M1-L-M2 in which M1 and M2, which may be identical or different, each represent, independently of one another, a monomer unit M and L represents a linker group linking M1 and M2 covalently, characterized in that said monomer unit corresponds to the general formula M that follows: in which, * indicates the site of linkage between monomer unit M and linker L, - R1 represents. a group -NHCOPh, said phenyl being substituted with an oxygen atom, so that the oxygen atom is the site of linkage between the monomer unit and the linker L; This group can be designated -NHCOPhO *, or. an aryl group, in particular phenyl, or a heteroaryl group, said group being substituted with a group selected from a divalent oxygen atom so that the oxygen atom is the site of linkage between the monomer unit and the linker L, or an amide group -CONH * -, so that the nitrogen atom is the binding site between the monomer unit and the linker L, - R2 represents an alkyl group, - R3 represents a hydrogen atom or a linear alkyl group, branched, cyclic or partially cyclic, - R4 represents a hydrogen atom or an alkyl or -alkyl-COOR5 group, R5 representing a hydrogen atom or an alkyl group, - L is chosen from the radicals having the following formulas: ** Formulas ** in which - * indicates the connection atom of L with the monomer unit M in the substituent R1, - n represents an integer from 0 to 5, - m represents an integer from 1 to 5, - r represents an integer from 1 to 6, - R2 'and R2 ", which they may be identical or different, they represent a linear alkyl radical having 1 to 5 carbon atoms, and which may be optionally bonded to form a ring, - R6 represents a (C1-C4) alkyl group, optionally substituted with one or more substituents selected from: - an aryl or heteroaryl group, optionally substituted with a group selected from a hydroxyl, amine or NR6'R6 "group, R6 'and R6" being chosen, which may be identical or different, from a hydrogen atom or a linear, branched or cyclic (C1-C4) -alkyl group, - a heterocycloalkyl group comprising at least one heteroatom chosen from a nitrogen atom and an oxygen atom optionally substituted with a linear or branched alkyl group, - an NR6 'group R6 ", choosing R6 'and R6", which may be identical or different, between a hydrogen atom or a linear, branched or cyclic (C1-C4) alkyl group, - an optionally O (C1-C4) alkyl group substituted with a hydro group xyl, in the form of a base or a salt by addition with an acid.

Description

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DESCRIPTION

FGF receptor agonist dimeric compounds (FGFR), procedure for their preparation and therapeutic use thereof

The object of the present invention are novel heterodical compounds that induce dimerization of the fibroblast growth factor receptor (FGFR), the process for its preparation and the therapeutic uses thereof. The object of the present invention are, in particular, new compounds with a dimeric structure such as FGFR agonists.

FGFs are a family of polypeptides synthesized by a large number of cells during embryonic development and by cells of adult tissues in various pathological conditions.

FGF2 (or b-FGF) is the first and best characterized of these growth factors. FGF2 is an 18 kDalton (kDa) protein, which induces proliferation, migration and protease production by numerous cells and, in particular, endothelial cells, fibroblasts, smooth muscle cells or, alternatively, bone cells. FGF2 interacts with the cells by means of two kinds of receptors, high affinity tyrosine kinase receptors (FGFRs) and low affinity heparan sulfate proteoglycan (HSPG) type receptors located on the cell surface and in extracellular matrices. Therefore, FGF2 and its receptors represent very relevant targets for therapies aimed at the activating processes of angiogenesis and regeneration of smooth muscle cells, bone cells and hair follicle cells.

In addition, it is known that the cell surface receptor tyrosine kinases transmit information through the plasma membrane, in particular through mechanisms of dimerization of the extracellular domains of these receptors.

Known ligands, capable of activating these dimerization mechanisms are typically natural compounds such as FGFs, PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor), EPO (erythropoietin), G-CSF (stimulating factor granulocyte colonies), TPO (thrombopoietin), certain cytokines or insulin.

B. Seed (Chemistry and Biology, November 1994, 1, 125-129), establishes the general principle that it is possible to build cell receptor agonists by dimerizing antagonists. However, there is no described example of a synthetic molecule constructed in accordance with this concept. Articles such as S A. Qureshi (PNAS, 1999, vol. 96, No. 21, 12156-12161), B E. Welm (The Journal of cell biology, 2002, vol. 157, 4, 703714), K. Koide (J. Am. Chem. Soc., 2001, 123, 398-408) describe non-peptide compounds or chemical dimerization inducers (CID), these compounds acting on the chimeric receptors and not on the natural receptors. They do not present any results that demonstrate that a CID makes it possible to activate the signaling pathway of a natural receptor.

In vertebrates there are 22 members in the family of FGFs with a molecular weight between 17 and 34 kDa and that share between 13% and 71% homology. These FGFs are highly conserved, both at the gene level and at the amino acid sequence level. (D Ornitz. And N. Fibroblast growth factors. Genome Biology, 30005,13005,12, 2001). FGFs interact with cells by means of high affinity receptor tyrosine kinases (FGF-R1, -R2, -R3, -R4). The expression of FGFs suggests that they have an important role in development. Among the FGF family, FGF-2 is the FGF that has been described more widely. It is an 18 kDa protein that induces the proliferation, migration and production of proteases in various types of cells such as endothelial cells, smooth muscle cells, fibroblasts, pericytes, osteoblasts or hair follicle cells. Therefore, the main therapeutic sectors in which FGF2 is involved include neuronal and cardiovascular physiology, nerve regeneration, nociception, tissue repair, homeostasis and bone repair.

Therefore, FGF2 and its receptors represent very relevant targets for therapies aimed at inducing angiogenesis and arteriogenesis processes (Khurana, R. and Simons, M. Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease. Trends Cardiovasc Med 13 , 116-22, 2003). When a blood vessel is clogged, an ischemic phase is observed that induces a decrease in arterial circulation in an organ, thereby leading to a decrease in the concentration of oxygen in the damaged tissues. It has been shown in vitro and in vivo that several growth factors stimulate angiogenesis and arteriogenesis processes. FGF2 also induces neovascularization in vivo and also the development of collateral vessels after ligation of an artery in pharmacological models.

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Several evidences show that FGF2 is also involved in the differentiation of angioblasts in epithelial progenitor cells and, therefore, participates in revascularization after occlusion (Burger, PE et al. Fibroblast growth factor receptor-1 is expressed by endothelial progenitor cells Blood 100, 3527-35, 2002). Therefore, strategies aimed at increasing the response of vascular tree cells are appropriate strategies to increase post-ischemic revascularization and, in particular, cardiac or coronary artery (Freedman, SB and Isner, JM Therapeutic angiogenesis for ischemic cardiovascular disease. J Mol Cell Cardiol 33, 379-93, 2001; Freedman, SB and Isner, JM Therapeutic angiogenesis for coronary artery disease. Ann Intern Med 136, 54-71,2002).

Regarding the treatment of cardiac ischemia, one of the most promising clinical trials is a trial in which FGF2 was sequestered in alginate microspheres in the presence of heparin (Laham, RJ et al. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, doubleblind, placebo-controlled trial, Circulation 100, 1865-71, 1999). After 90 days, all patients treated with FGF2 showed no ischemic cardiac symptom. In comparison, in the control group, 3 of the 7 patients have persistent symptoms at 90 days, and 2 patients resorted to vascular surgery. Interestingly, the benefit of therapy was maintained after 3 years of follow-up. In addition, three clinical trials were carried out on the injection of FGF2 into the coronary artery in the treatment of coronary artery narrowing (Laham, RJ et al. Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study. J Am Coll Cardiol 36, 2132-9, 2000; Simons, M. et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double -blind, randomized, controlled clinical trial Circulation 105, 788-93, 2002; Unger, EF et al. Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am J Cardiol 85, 1414-9, 2000 The result of these three trials demonstrates that intra-coronary infusions of FGF2 are well tolerated and significantly improve the clinical condition of patients.

In another phase I clinical trial, patients with peripheral arterial disease leading to claudication received injections of FGF2 (Lazarous, DF et al. Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial. J Am Coll Cardiol 36, 1239-44, 2000). In this context, FGF2 was well tolerated in these patients and the clinical data suggest a beneficial effect of FGF2, particularly in the improvement of walking in patients with peripheral disease, for example Buerger's disease or obliterating thromboangeitis, which affects the structures. distal vascular and characterized by distal arteritis in the legs, accompanied by pain and ulceration.

In another context that requires improved angiogenesis it has only been clearly demonstrated in diabetic rats that the vascularization in the bioartificial pancreas was much greater when the pancreas was impregnated with microspheres that carry FGF2 (Sakurai, Tomonori; Satake, Akira, Sumi, Shoichiro, Inoue , Kazutomo, Nagata, Natsuki, Tabata, Yasuhiko The Efficient Prevascularization Induced by Fibroblast Growth Factor 2 With a Collagen-Coated Device Improves the Cell Survival of a Bioartificial Pancreas Pancreas 28 (3): e70-e79, April 2004) . Therefore, this revascularization improves the survival of implanted bioartificial pancreas and, consequently, graft survival. Therefore, FGFs seem to contribute to the improvement of bioartificial pancreatic graft survival implanted in diabetic patients and, more generally, seem to contribute to the improvement of graft revascularization and appear to be involved in graft survival.

In addition to the inducing effects of angiogenesis, FGF2 protects endothelial cells against inducers of apoptosis. It has now been clearly described that FGF2 is a survival factor for endothelial cells (Role of Raf in Vascular Protection from Distinct Apoptotic Stimuli: A Alavi, JD Hood, R. Frausto, DG Stupack, DA Cheresh: Science July 4, 2003: Vol. 301. No. 5629, pages 94-96). The acute respiratory distress syndrome (ARDS) is characterized by cardiovascular and neuropsychiatric problems. In the context of cardiovascular problems, patients present a considerable vascular lesion and, in particular, a high level of induction of endothelial cell apoptosis. Recently, Hamacher et al. have shown that bronchoalveolar lavage fluids of patients suffering from ARDS exhibit pro-apoptotic activity against microvascular endothelial lung cells (Tumor necrosis factor-alpha and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar lavages of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. Sep. 1, 2002; 166 (5): 651-6: Hamacher J, Lucas R, Lijnen HR, Buschke S, Dunant Y, Wendel A, Grau GE, Suter PM, Ricou B. ).

Pre-eclampsia is a pathological condition of the placenta that is associated with a deficiency in vascularization (Sherer, D. M. and Abulafia, O. Angiogenesis during implantation, and placental and early embryonic development. Placenta 22, 1-13, 2001). It is believed that these vascularization deficiencies are due to a deficiency in angiogenesis and to lead to disruptions at the level of the placenta that may result in the death of the fetus.

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Healing is a process of tissue regeneration that does not require treatment in most cases. However, complications such as infections or the appearance of a keloid scar may appear, which is a pathological scar characterized by a fold of fibrous consistency, or by skin retractions that result in a loss of skin elasticity. The healing phase takes place in 5 stages: the first phase is the inflammatory phase, which is the starting point for tissue repair. This inflammatory reaction causes vasodilation and increases the permeability of the lesion. The second phase is the angiogenesis phase, which allows the provision of nutrients and oxygen, essential for cells. The third phase is the migration phase: the tissue of renewal (and, therefore, granulation) is put in place: this is the beginning of the production of the scar. All connective tissue cells migrate to the center of the lesion, in particular, fibroblasts and keratinocytes. The fourth phase is the proliferation phase, which consists of a massive proliferation of connective tissue cells, and of fibers associated with the development of blood vessels. The final phase is the maturation phase, which is the longest phase: it lasts 18 to 24 days. The number of fibroblasts will then decrease, as will the number of blood vessels, in order to give rise to the end of healing. In the case of diabetic patients, healing is a slow and difficult process that exposes them to chronic wounds that are extremely difficult to heal, often becoming complicated by infectious phenomena that can lead to amputations in the second place. By virtue of their pleiotropic activities, FGFs participate in tissue repair, in particular, by activating keratinocytes and fibroblasts and participating in the phenomenon of angiogenesis. Therefore, FGFs seem to play a role in improving healing in healthy or diabetic patients, both from the point of view of rapid healing and from the point of view of scar quality. It has also been clearly described that the levels of growth factors involved in the healing phenomena, and in particular FGFs, decrease greatly with age. Therefore, in elderly patients, deficiencies and delays in healing are related to deficiencies in skin FGFs.

Glutamate is a supposed transmitter of dorsal ganglion neurons and bradykinin is a molecule produced during inflammation that can activate and sensitize nociceptive fibers. In this context, FGF2 could modulate inflammatory pain, even though no regulatory effect of FGF2 on nociceptive fibers has been demonstrated in vivo. However, it has been shown that FGF2 completely blocks the release of glutamate stimulated by bradykinin in vitro (Rydh-Rinder et al. (2001) Regul Pept 102: 69-79). Therefore, FGFS can play a role in nociception and chronic pain.

Peripheral neuropathy is an axonal or demyelinating attack on the motor nerve and / or the peripheral sensory nerve that leads to desensitization of the distal extremities. One of the consequences of nerve injury can be a perforating ulcer, which is to be feared in particular when there is considerable damage to deep sensitivity, since, in this case, body weight has a tendency to always be carried by The same support points. One of the main secondary complications of diabetes is the development of chronic peripheral neuropathy. In this context, it has been shown that FGF2 induces axonal regeneration that could be an therapy of choice in the treatment of peripheral nerve injury and, therefore, in peripheral neuropathy (Basic fibroblast growth factor isoforms promote axonal elongation and branching of adult sensory neurons in vitro Klimaschewski L, Nindl W, Feurle J, Kavakebi P, Kostron H. Neuroscience, 2004; 126 (2): 347-53).

It has been proposed that the FGF system is an essential system of muscle regeneration, and the survival and proliferation of myoblasts (Neuhaus, P. et al. Reduced mobility of fibroblast growth factor (FGF) -deficient myoblasts might contribute to dystrophic changes in the musculature of FGF2 / FGF6 / mdx triple-mutant mice. Mol Cell Biol 23, 6037-48,2003). FGF2 could be exploited in order to promote muscle regeneration, particularly in the case of sarcopenia, loss of smooth muscle functionality in the sphincters, and also for the survival and progression of transplanted myoblasts and, in particular, in the Duchenne muscular dystrophy. It also appeared that growth factors such as VEGF or FGF2 improved myocardial perfusion after ischemia (Hendel, RC et al. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. Circulation 101 , 118-21, 2000). In addition, the vascular network is essential for tissue development and preservation. By promoting the supply of nutrients, oxygen and cells, the blood vessels help maintain the functional and structural integrity of the tissues. In this context, angiogenesis and vasculogenesis make it possible to preserve and perfuse tissues after ischemia. Angiogenic growth factors such as FGF2, therefore, promote revascularization for tissue regeneration. Therefore, FGF2, acting directly on skeletal muscle cells and angiogenesis, will have an effect on the regeneration of dystrophic or normal muscles (Fibbi, G., D'Alessio, S., Pucci, M., Cerletti, M. and Del Rosso, M. Growth factor-dependent proliferation and invasion of muscle satellite cells require the cell-associated fibrinolytic system. Biol Chem 383, 127-36, 2002).

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Among the main growth factors, it has now been clearly established that the systematic administration of FGF2 facilitates bone repair after fracture (Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2. Kawaguchi

H, Nakamura K, Tabata Y, Ikada Y, Aoyama I, Anzai J, Nakamura T, Hiyama Y, Tamura M. J Clin Endocrinol Metab. 2001 Feb; 86 (2), 875-880). The local application of FGF2 in jelly matrices accelerates bone repair in primates, suggesting the clinical utility of FGF2 in the treatment of fractures.

The excess of endogenous regulation of FGF7 (or KGF) and FGF18 seems to be an important mechanism to promote proliferation, migration and protection of hair follicles in pathological cases or after treatment with a cytotoxic agent (Comprehensive Analysis of FGF and FGFR Expression in Skin: FGF18 Is Highly Expressed in Hair Follicles and Capable of Inducing Anagen from Telogen Stage Hair Follicles, Mitsuko Kawano, Akiko Komi-Kuramochi, Masahiro Asada, Masashi Suzuki, Junko Oki, Ju Jiang and Toru Imamura).

The applicant has now found new synthetic molecules capable of inducing the dimerization of the FGF receptor and which may be useful in numerous mechanisms in which FGFRs such as angiogenesis, or regeneration of smooth muscle, bone or hair follicle cells are involved.

The objective of the invention is to propose new agonist compounds of the FGF receptor with a dimeric structure.

These compounds carry out the dimerization of FGF receptors, which causes their activation and, in the end, cellular activation.

An object of the present invention are agonist compounds of FGF receptors that correspond to the general formula:

M1-L-M2

in which Mi and M2, which may be identical or different, each represents, independently of one another, a monomer unit M and L represents a linker group that links Mi and M2 covalently.

The agonists of the formula M1-LM2 according to the invention comprise two units of monomers of general formula M, designated Mi and M2, which can be identical or different, chosen as each having an antagonistic activity of the FGFR.

An object of the present invention are FGF receptor agonist compounds as defined above, characterized in that said monomer unit corresponds to the general formula M that follows:

image 1

in which,

* indicates the link site between monomer unit M and linker L,

- Ri represents

. a group -NHCOPh, said phenyl being substituted with an oxygen atom, so that the oxygen atom is the site of linkage between the monomer unit and the linker L; This group can be designated -NHCOPhO *, or

. an aryl group, in particular phenyl, or a heteroaryl group, said group being substituted with a group selected from a divalent oxygen atom so that the oxygen atom is the site of linkage between the monomer unit M and the linker L, or an amide group -CONH * -, so that the nitrogen atom is the site of union between the monomer unit and the linker L,

- R2 represents an alkyl group, advantageously a methyl group,

- R3 represents a hydrogen atom or a linear, branched, cyclic or partially alkyl group

dclico,

- R4 represents a hydrogen atom or an alkyl group or -alkyl-COORs, R5 representing a hydrogen atom or an alkyl group,

5 in the form of a base or salt by addition with an acid or with a base.

L represents a linker group that binds M1 and M2 covalently such that the distance between the two monomer units M1 and M2 allows the dimerization of two FGF receptors. Said linker group comprises 2 to 20 links. Said linker group L comprises more particularly 11 to 20 links. The term "links" is intended to mean only the links between atoms that make it possible to connect the 10 monomer units M1 and M2.

The linker group L is characterized by a flexibility that allows each of the monomer units of the compound of formula M1-LM2 to establish contact with the extracellular binding sites of the transmembrane FGFR receptors.

L is attached, firstly, to a monomer unit of formula M1 by an atom placed in substituent R1 and 15, secondly attached to the other monomer unit of formula M2 by an atom placed in substituent R1, M1 and M2 being identical or different.

The object of the present invention are more particularly compounds as defined above, characterized in that L connects the 2 monomer units M1 and M2 through the radical R1.

The connection atoms found in the substituent R1 of the monomer unit of formula M can be represented by oxygen or nitrogen atoms.

The unions between L and the monomer units can be represented by C-O or C-N bonds.

The linker groups L suitable for the invention can be chosen from structures of the formulas (A) to (E) as defined below.

These compounds of formula M1-LM2 may exist in the form of bases or in salified form with acids or bases, in particular particular pharmaceutically acceptable acids or bases. Sales by addition of this type are part of the invention. Mention may be made, in particular, of salts of D, L-lysine or sodium salts.

In the context of the present invention, and unless otherwise indicated in the text:

- the term alkyl is intended to mean: a hydrocarbon based, linear or aliphatic group

branched comprising 1 to 4 carbon atoms; by way of example, mention can be made of groups

Methyl, ethyl, propyl and pentyl;

- the term "heterocycloalkyl" is intended to mean: a cyclic alkyl group comprising 3 to 8 members, comprising between 3 and 6 carbon atoms and one or more heteroatoms, for example 1 or 2 heteroatoms such as nitrogen and / or oxygen, said heterocycloalkyl group being optionally substituted with one or more halogen atoms and / or alkyl groups. As an example you can mention the groups

Piperazinyl, pyrrolidinyl and piperidinyl;

- the term halogen is intended to mean: an atom of chlorine, fluorine, bromine or iodine;

- the term haloalkyl is intended to mean: an alkyl chain in which all or some of

hydrogen atoms are replaced with halogen atoms, such as fluorine atoms;

- the term aryl is intended to mean: a dical aromatic group comprising between 5 and 10 40 carbon atoms, for example a phenyl group; Y

- the term heteroaryl is intended to mean: a cyclic aromatic group comprising between 3 and 10 atoms, including one or more heteroatoms, for example between 1 and 4 heteroatoms such as nitrogen or oxygen, this group comprising one or more, preferably 1 or 2 rings The heteroaryls are optionally substituted with one or more alkyl groups or an oxygen atom. As an example, mention can be made of

Thienyl, pyridinyl, pyrazolyl, imidazolyl and triazolyl groups.

The object of a subgroup according to the present invention is more particularly agonist compounds of FGF receptors as defined above, characterized in that said monomer unit corresponds to the general formula M that follows:

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image2

in which,

* indicates the link site between monomer unit M and linker L,

- Ri represents

- a group -NHCOPh, said phenyl being substituted with an atom of

oxygen, so that the oxygen atom is the binding site between the monomer and the linker L; This group can be designated -NHCOPhO *, or

- a phenyl group, said group being substituted with a group chosen from a

divalent oxygen atom, so that the oxygen atom is the binding site between the monomer unit M and the linker L, or an amide group -CONH * -, so that the nitrogen atom is the site of union between the monomer unit and linker L,

- R2 represents a methyl group,

- R3 represents a hydrogen atom,

- R4 represents an alkyl-COOR5 group, R5 representing a hydrogen atom, in the form of a

base or salt by addition with an acid or a base.

The object of another subgroup according to the invention is particularly above, which comprise the monomer unit of formula M in which:

Ri represents a group -NHCO-PhO *, -Ph-O * or Ph-CONH *, in the form of a base or a salt by addition with an acid or with a base.

The object of another subgroup according to the invention is particularly above, which comprise the monomer unit of formula M in which:

Ri represents a group -NHCO-PhO *, -Ph-O * or Ph-CONH *,

R2 represents a methyl group,

in the form of a base or salt by addition with an acid or with a base.

The object of another subgroup according to the invention is particularly above, which comprise the monomer unit of formula M in which:

R3 represents a hydrogen atom,

R4 represents an alkyl-COOR5 group, R5 representing a hydrogen atom or an alkyl group, in particular a hydrogen atom,

in the form of a base or a salt by addition with an acid or a base.

The object of another subgroup according to the invention is more particularly compounds of Mi-LM2tal formula as defined above, with M1 being identical to M2.

The linker groups L can be chosen from the radicals having the following formulas:

image3

compounds as defined

compounds as defined

compounds as defined

image4

image5

image6

in which

5 * indicates the connection atom of L with the monomer unit M in the Ri substituent,

n represents an integer from 0 to 5, m represents an integer from 1 to 5, r represents an integer from 1 to 6,

R2 'and R2 ", which may be identical or different, represent a linear alkyl radical having 1 to 5 carbon atoms, and which may optionally be linked to form a ring,

R6 represents a (C1-C4) alkyl group, preferably a (C1-C2) alkyl group, optionally substituted with one or more substituents selected from:

- an aryl or heteroaryl group, optionally substituted with a group selected from a hydroxyl, amine or NR6'R6 "group, with R6 'and R6" being chosen, which may be identical or different, from a hydrogen atom or a group -

(C1-C4) linear, branched, or dichloric alkyl,

- a heterocycloalkyl group comprising at least one heteroatom chosen from a nitrogen atom and an oxygen atom optionally substituted with a linear or branched alkyl group,

- a group NR6'R6 ", choosing R6 'and Re", which may be identical or different, between a hydrogen atom or a linear, branched or cyclic (C-i-C4) alkyl group,

20 - an O (C1-C4) alkyl group optionally substituted with a hydroxyl group,

in the form of a base or a salt by addition with an acid.

The object of another subgroup according to the invention is the linker groups L having the above formulas, in which:

* indicates the connection atom of L with the monomer unit M in the substituent R1,

25 n represents 2 or 3,

m represents 1, 2, 3 or 5, r represents 2, 4 or 6,

R2 'and R2 ", which may be identical or different, represent a linear alkyl radical having 1 to 5 carbon atoms, and which may optionally be linked to form a ring,

R6 represents a (C1-C4) alkyl group, preferably a (C1-C2) alkyl group, optionally substituted with one

or more substituents chosen from:

- an aryl or pyridine group optionally substituted with an NRe'Re "group, representing R6 'and R6", which may be identical or different, a linear (C1-C4) alkyl group,

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- a heterocycloalkyl group comprising at least one heteroatom chosen from a nitrogen atom and an oxygen atom optionally substituted with a linear or branched alkyl group,

- a group NR6'R6 ", representing R6 'and Ra", which may be identical or different, a (C1-C4) alkyl group

linear,

- an O-C1-C4 alkyl group optionally substituted with a hydroxyl group, in the form of a base or a salt by addition with an acid.

The object of another subgroup according to the invention is particularly compounds as defined above, so that linker group L is radical A, in the form of a base or a salt by addition with an acid or a base.

The object of another subgroup according to the invention is particularly compounds as defined above, so that linker group L is radical B, in the form of a base or salt by addition with an acid or a base.

The object of another subgroup according to the invention is particularly compounds as defined above, so that linker group L is radical C, in the form of a base or salt by addition with an acid or a base.

The object of another subgroup according to the invention is particularly compounds as defined above, so that linker group L is radical D, in the form of a base or salt by addition with an acid or a base.

The object of another subgroup according to the invention is particularly compounds as defined above, so that linker group L is radical E, in the form of a base or salt by addition with an acid or a base.

The subgroups defined above, taken separately or in combination, are also part of the invention.

Among the compounds of the invention, mention may be made, in particular, of the following compounds:

- Compound 1: 2,2 '- {oxibis [ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-) acid

diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-a, 3 (2H) -dyl)]} diacetic;

- Compound 2: 2,2 '- {oxibis [ethane-2,1-diyloxyethane-2,1-diyloxybenzene-3,1-diyl (2-methylindolizine-1,3-) acid

diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-a, 3 (2H) -diyl)]} diacetic;

- Compound 3: 2,2 '- {ethane-1,2-diylbis [oxethane-2,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl (2,4-dioxo) acid -1,4-dihydroquinazoline-a, 3 (2H) -diyl)]} diacetic;

- Compound 4: 2,2 '- {hexane-1,6-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylindolizine-1,3- acid)

diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-a, 3 (2H) -diyl)]} diacetic;

- Compound 5: 2,2 '- {butane-1,4-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylindolizine-1,3-) acid

diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-a, 3 (2H) -diyl)]} diacetic;

- Compound 6: 2,2 '- {hexane-1,6-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-3,1-diyl (2-methylindolizine-1,3-diyl) carbonyl acid (2,4-dioxo-1,4-dihydroquinazoline-a, 3 (2H) -diyl)]} diacetic;

- Compound 7: 2,2 '- {butane-1,4-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-3,1-diyl (2-methylindolizine-1,3-) acid

diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-a, 3 (2H) -diyl)]} diacetic;

- Compound 8: 2,2 '- ({[2- (2-hydroxyethoxy) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) acid carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl) j) diacetic;

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- Compound 9: 2,2 '- {(ethylimino) bis [pentane-5,1-diMoxybenzene-4,1-diyl (2-metMindolizine-1,3-diyl) carbonyl (2,4-dioxo-1, 4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic;

- Compound 10: 2,2 '- ({[2- (morpholin-4-yl) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindoNzine-1,3-] acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoNna-7.3 (2H) -diN)]) diacetic;

- Compound 11: 2,2 '- ({[2- (4-methyl-piperazin-1-yl) etN] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-

methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]) diacetic;

- Compound 12: 2,2'- {[(pyridin-4-ylmethyl) imino] bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl (2 , 4 dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic;

- Compound 13: 2,2 '- ({[4- (dimetNamino) bencN] imino} bis [pentane-5,1-diNoxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl acid ( 2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]) diacetic;

- Compound 14: 2,2 '- ({[2- (dietNamino) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindoNzine-1,3-diyl) carbonyl acid ( 2,4-dioxo-1,4-dihydroquinazoNna-7.3 (2H) -diN)]) diacetic;

- Compound 15: 2,2 '- {piperazine-1,4-diylbis [propane-3,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-] acid

diyl) carboml (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic;

- Compound 16: acid [7 - ({1- [4 - ({9- [4- (3 - {[3- (carboxymethyl)) -2,4-dioxo-1,4-dihydroquinazolin-7 (2H) - il] carbonyl} -2-methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5-phosfanon-1-yl} carbamoyl) phenyl] -2-methylindolizin-3- yl} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) yl] acetic acid;

- Compound 17: 2,2 '- {ethane-1,2-diylbis [oxethane-2,1-diylcarbamoylbenzene-4,1-diyl (2-methylindolizine-1,3-) acid

diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic;

- Compound 18: 2,2 '- {ethane-1,2-diylbis [oxethane-2,1-diylcarbamoylbenzene-3,1-diyl (2-methylindoNzine-1,3-) acid

diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic;

- Compound 19: acid [7 - ({1- [3 - ({9- [3- (3 - {[3- (carboxymethyl)) -2,4-dioxo-1,4-dihydroquinazolin-7 (2H) - il] carbonN} -2-methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5-phosfanon-1-yl} carbamoyl) phenyl] -2-methylindolizin-3- yl} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) yl] acetic acid;

- Compound 20: 2,2 '- {ethane-1,2-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-3,1-diylcarbonylimino (2- methylindolizine-1,3-diyl) carbonyl acid (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic.

It should be noted that the above compounds were named using the IUPAC nomenclature through ACDLABS 10.0 ACD / name (Advanced Chemistry Development) or AutoNom software (Beilstein Informations system).

In the following, the expression "protective group (PG)" is intended to mean a group that makes it possible, first, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, secondly, to regenerate the reactive function intact at the end of the synthesis. Examples of protective groups and also protection and deprotection methods are given in "Protective Groups in Organic Synthesis", Green et al., 4th edition (John Wiley & Sons, Inc., New York).

In the following, the expression "labile group (LG)" is intended to mean a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with the output of a pair of electrons. Therefore, this group can easily be replaced by another group in a substitution reaction, for example. Such labyl groups are, for example, halogens or an activated hydroxyl group, such as a mesyl, tosyl, triflate, acetyl, etc. Examples of labile groups and also references for their preparation are given in "Chemistry Advanced Organic", J. March, 5th edition, Wiley Interscience, pags. 310-316.

According to the invention, the compounds of general formula (I) can be prepared according to the procedure that follows.

Preparation of monomer units

image7

Scheme 1 illustrates the synthesis of the monomer units of formula (VII). The acid chloride of formula (I) is obtained from 4 - [(femlcarboml) ammo] benzene-1,3-dicarboxylic acid [CAS 121732-46-5; C. K. Lee and Y. M. Ahn, 5 Journal of Organic Chemistry, 1989, 54 (15), 3744-7] by treatment with thionyl chloride in an inert solvent such as 1,2-dichloromethane, by reflux heating. The indolizine of formula (II), with R2 as previously defined, reacts with the acid chloride of formula (I) in an inert solvent, such as DCM or THF, optionally in the presence of a weak base, such as triethylamine, from 0 ° C to room temperature, to give the compound of formula (III). The regioselective introduction of a halogen atom (designated X) at position 10 of the indolizine of formula (III) is carried out through an aromatic electrophilic substitution reaction with reactants such as, for example, iodine, NIS, NBS or bromine, optionally in the presence of a weak base such as NaHCO3 in an inert solvent such as anhydrous or aqueous MeOH, dioxane or DCM, at room temperature, to give the halogenated derivative of formula (IV). Hydrolysis of the compound of formula (IV) in an aqueous medium of basic character with, for example, sodium hydroxide or potassium hydroxide, optionally in the presence of a solvent solvent such as NMP, and by refluxing, gives the anthramic acid of formula (V).

The carboxylic acid of formula (V) can be activated using a reagent such as BOP or PyBOP, in the presence of a weak base such as, for example, triethylamine from 0 ° C to room temperature in an inert solvent such as DMF or THF Then, it is reacted with protected glycine in the form of an ester with a PG1 group chosen from an alkyl group such as a methyl group or a tert-butyl group and a benzyl group, to give the compound of formula (VI). The reaction of ethyl chloroformate with the compound of formula (VI) in the presence of a weak base such as triethylamine, gives an intermediate carbamate compound which, after the addition of a base such as DBU or DABCO, gives the formula quinazolindione (VII).

image8

The halogenated derivative of formula (VII) can be used in an organometallic coupling reaction catalyzed with palladium using, for example, PdCl2 (dppf), either with aryl boronic acids or esters in the presence of a weak base such as, for example , potassium phosphate in an inert solvent such as DMF, while heating at 60-120 ° C, to give the compound of formula (VIII) comprising a group W representing a hydroxyl group or an optionally protected carboxy group, PG2 being an alkyl group selected from a tert-butyl group and a benzyl group, or an optionally protected group -O (CH2) m-carboxy with my PG2 as defined above.

When the compound of formula (VIII) comprises a carboxy group protected with PG2, it is treated, either in an acidic medium with, for example, TFA in dry conditions at room temperature, or by hydrogenolysis in the presence of Pd / C so that preserves the group PG1, to give the carboxylic acid of formula (VIII).

Scheme 3

image9

The compound of formula (VIII) when W is a hydroxyl group, can react with an electrophile of formula (LG) -15 (CH2MLG '), with previously defined m and also LG and LG', which can be identical or different, represent a

halogen atom or an activated hydroxyl group such as a mesyl, tosyl, triflate or acetyl group, after deprotonation with a base such as, for example, sodium hydride, in an inert solvent such as DMF or THF, at room temperature , to give the compound of formula (IX).

image10

The halogenated compound of formula (VII) can be used in a coupling reaction with benzophenonaimine. This coupling is catalyzed with palladium using, for example, Pd (OAc) 2, optionally in the presence of a ligand such as, for example, Xantphos, in the presence of a base such as cesium carbonate, while heating to 60 -120 ° C, to give the imine of formula (X) which, after treatment in an acid medium with, for example, hydrochloric acid, gives the amine of formula (XI) at room temperature.

Preparation of the dimeros

image11

The halogenated derivative of formula (VII) can be used in a coupling reaction catalyzed with organometallic palladium 10 using, for example, PdCh (dppf) with aryl boronic acids of formula (XII) when L represents linker A as described in application WO2007080325, in the presence of a weak base such as, for example, potassium phosphate in a solvent such as DMF, while heating at 60-120 ° C, to give the compound of formula (XIII). Saponification of the esters of formula (XIII) gives the compounds of the invention.

image12

When the compound of formula (VIII) has an unprotected carboxy group W, it can be coupled to a diamine of formula H2N-L-NH2 after activation with, for example, BOP or PyBOP in the presence of a weak base such as triethylamine in a solvent such as THF or DMF, at a temperature ranging from 0 ° C to room temperature, to give the dfimers of formula (XIV). Saponification of the esters of formula (XIV) 5 provides the compounds of the invention. The same type of reaction can be applied to the compounds of formula (VIII) when W = -O (CH2) mCO2H.

image13

The compound of formula (IX) can be used in a nucleophilic substitution reaction with a primary amine R6-NH2 in the presence of a weak base such as potassium carbonate, at room temperature, to give the dimer of formula (XV) or the secondary amine of formula (XVI) when the R6-NH2 amine is present in large excess. The isolated amine (XVI) can react with a stoichiometric amount of the compound of formula (IX) in the presence of a weak base such as, for example, potassium carbonate, at room temperature, to give the formula dimer (XV). Saponification of the esters of formula (XV) gives the compounds of the invention.

image14

The amine of formula (XI) can be coupled to a dicarboxylic acid of formula (XVII) activated with, for example, BOP or PyBOP in the presence of a weak base such as triethylamine, in a solvent such as THF or DMF, to a temperature ranging between 0 ° C and room temperature, to give the formula dimmers (XVIII). Saponification of the esters of formula (XVIII) provides the compounds of the invention.

In the above schemes, the starting compounds and the reactants, when the method for their preparation is not described, are commercially available or described in the literature, or they can be prepared according to methods described therein or which They are known to those skilled in the art.

According to another of its aspects, an object of the invention is also the compounds of formulas (II) to (XVIII) 5 defined above. These compounds are of use as intermediate synthetic compounds for the compounds of formula (I).

The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and merely illustrate the present invention. The numbers of the exemplified compounds refer to those given in the table hereinafter, which shows the chemical structures and physical properties of some compounds according to the invention.

The following abbreviations and molecular formulas are used:

EtAOc = ethyl acetate

BOP = benzotriazol-1-yloxytris (dimethylamino) phosphonium tetrafluorophosphate DABCO = 1,4-diazabicyclo [2.2.2] octane 15 DBU = 2,3,4,6,7,8,9,10-octahydropyrimido [1,2 -a] azepine

DCM = dichloromethane DMF = W, W-dimethylformamide EtOH = ethanol h = hour (s)

20 KHSO4 = potassium hydrogen sulfate

LCMS = liquid mass spectroscopy chromatography

MeOH = methanol

MeTHF = 2-methyltetrahydrofuran

min = minute (s)

25 mL = milliliter (s)

(m) mol = (mili) mol (s)

NaHCO3 = sodium hydrogen carbonate NBS = W-bromosuccinimide NIS = W-iodosuccinimide 30 NMP = N-methyl-2-pyrrolidone

Pd (PPh3) 4 = tetrakis (triphenylphosphine) palladium (0)

PdCl2 (dppf) = 1,1'-bis (diphenylphosphino) ferrocene dichloropaladium (II) ppm = parts per million

PyBop = benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate

35 NMR = nuclear magnetic resonance

HBTU = 2- (1 H -benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate TFA = trifluoroacetic acid THF = tetrahydrofuran

Xantphos = 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene 40 As follows:

- Proton magnetic resonance spectra (1 H NMR), as described below, are recorded at 400 MHz or 500 MHz in DMSO-d6, using the DMSO-d6 peak as a reference. The chemical shifts 6 are expressed in parts per million (ppm). The observed signals are expressed as follows: s = singlet; d = double; t = triplet; m = unresolved peak or br. s. = wide singlet.

Example 1: Lysine acid salt 2,2 '- {oxibis [ethane-2,1-diMoxietane-2,1-diyloxybenzene-4,1-diyl (2-methylmdolizma-

1,3-diyl) carboml (2,4-dioxo-1,4-dihydroqumazolma-6,3 (2H) -dMl)]} diacetic (compound No. 1).

Stage 1.1 Chloride of (2E) -2 - [(EH4-methylidene-6-oxo-2-feml-4H-1,3-oxazm-5 (6H) Miden) methyl] but-2-enoflo

Thionyl chloride (16.9 mL, 231 mmol) and 0.5 mL of DMF were added to a suspension of 4- [(phenylcarbonyl) amino] benzene-1,3-dicarboxylic acid [CAS 121732-46-5; C. K. Lee and Y. M. Ahn, Journal of Organic

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Chemistry, 1989, 54 (15), 3744-7] (24.7 g, 92.61 mmol) in 310 mL of 1,2-dichloroethane. The mixture is heated at reflux for 4 h and then concentrated to dryness. The residue obtained is dissolved in toluene and then concentrated to dryness (3 times). The white solid is collected in diisopropylether, filtered and dried in vat to give 26 g (98%) of a white powder.

1H NMR [(CDa) 2SO, 250 MHz]: 6 ppm 13.13 (br s., 1 H) 8.63 (d, 1 H) 8.41 (dd, 1 H) 8.21-8.29 (m, 2 H) 7.82 (d, 1 H) 7.58-7.77 (m, 3 H)

Stage 1.2 (£ 5) -4-methylidene-5 - {(£ 2) -2 - [(2-methylindolizin-3-yl) carbonyl] but-2-en-1-ylidene) -2-phenyl-4, 5-dihydro-6H-

1,3-oxazin-6-one

A solution of 2-methylindolizine (11.5 g, 87.7 mmol) in 35 mL of THF is added dropwise to a suspension of chloride of (2E) -2 - [(E) - (4-methylidene-6 -oxo-2-phenyl- (6-oxazin-4H-1,3-oxazin-5 (6H) ylidene) methyl] but-2-enono (25 g; 87.7 mmol) in 140 mL of THF at 0 ° C under nitrogen After 18 h stirring at room temperature, the reaction medium is diluted in ethyl acetate, and the solution is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate and concentrated to dryness The residue obtained is purified by flash chromatography on silica (DCM) to give 22.75 g (69%) of a yellow powder.

[M + H] + = 381

Stage 1.3 (£ 5) -5 - {(£ 2) -2 - [(1-bromo-2-methylindolizin-3-yl) carbonyl] but-2-en-1-ylidene} -4-methylidene-2- phenyl-4,5-

dihydro-6H-1,3-oxazin-6-one

W-Bromosuccinimide (10.64 g, 59.8 mmol) is added portionwise to a solution of (5E) -4-methylidene-5 - {(2E) -2- [(2-methylindolizin-3-yl) carbonyl ] but-2-en-1-ylidene} -2-phenyl-4,5-dihydro-6H-1,3-oxazin-6-one (22.8 g; 59.8 mmol) in 350 mL of DCM and 105 mL of NMP. After 10 min of stirring at room temperature, the yellow precipitate formed is filtered off, washed with DCM and dried in a vacuum to give 23.2 g (85%) of the yellow powder.

[M + H] + = 460

Step 1.4 2-amino-5 - [(1-bromo-2-methylindolizin-3-yl) carbonyl] benzoic acid

La (5E) -5 - {(2E) -2 - [(1-bromo-2-methylindolizin-3-yl) carbonyl] but-2-en-1-ylidene} -4-methylidene-2-phenyl-4 , 5-dihydro-6H-1,3-

Oxazin-6-one (18.6 g; 40.4 mmol) is added in portions to potassium hydroxide (22.7 g; 0.40 mol) in 100 mL of water and 140 mL of NMP. The reaction mixture is heated at reflux for 18 h, cooled to room temperature and poured into a solution of hydrochloric acid (1 M). The yellow precipitate formed is filtered and dried in vacuo to give 16.5 g (99%) of a yellow powder.

[M + H] + = 374

Step 1.5 N - ({2-ammo-5 - [(1-bromo-2-methylmdoNzm-3-M) carboml] feml} carboml) methyl glycinate

Triethylamine (7.34 mL; 52.3 mmol) and PyBOP (9.97 g; 19.2 mmol) are added to a solution of 2-amino-5 - [(1- bromo-2-methylindolizin-3- acid il) carbonyl] benzoic acid (6.5 g; 17.4 mmol) in 58 mL of NMP at 0 ° C under nitrogen. After 30 min of stirring at 0 ° C, glycine medical ester hydrochloride (2.4 g; 19.2 mmol) is added. After 1 h of stirring at room temperature, the reaction medium is processed in a saturated aqueous solution of sodium hydrogen carbonate. The yellow precipitate formed is filtered off and dried in vacuo to give 6.45 g (83%) of a yellow powder.

[M + H] + = 444

Step 1.6 {6 - [(1-bromo-2-methylmdolizm-3-N) carboml] -2,4-dioxo-1,4-dihydroqumazolm-3 (2H) -M} methyl acetate

Ethyl chloroformate (1.3 mL; 13.5 mmol) is added dropwise to a solution of W - ({2-amino-5 - [(1-bromo-2-methylindolizin-3-yl) carbonyl] phenyl } Carbonyl) methyl glycinate (2 g; 4.5 mmol) in 9 mL of pyridine at 0 ° C. After 15 min stirring at room temperature, the reaction medium is concentrated to dryness and then diluted with ethyl acetate. The solution is washed with a 0.1 M hydrochloric acid solution and a saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The yellow solid obtained is dissolved in 20 mL of anhydrous tetrahydrofuran and heated to reflux in the presence of diaza (1,3) bicyclo [5,4,0] undec-7-ene (1.35 mL; 9 mmol) for 1 h. The reaction medium is diluted with ethyl acetate, washed with a 0.1 M hydrochloric acid solution and a saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness to give 2 g (95% ) of a yellow powder.

[M + H] + = 470

Step 1.7 2,2'-Oxybis [{ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1, 4-dihydroqumazolma-6.3 (2H) -diyl)]} methyl diacetate

{6 - [(1-Bromo-2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} methyl acetate (0.34 g; 0, 74 5 mmol; 2 eq), [oxybis (ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4,1-diyl)] diboronic acid [CAS 944446-98-4; WO 2007080325 A1] (0.16 g; 0.37 mmol), a molar solution of tribasic potassium phosphate (2.2 mL; 2.21 mmol), 9 mL of DMF and the PdCh catalyst (dppf) ( 0.08 g; 0.11 mmol) are successively introduced into a reactor under argon. The reaction mixture is heated at 90 ° C for 24 h, cooled to room temperature and concentrated to dryness. The residue obtained is purified by preparative HPLC on Kromasil C18 reverse phase [A 10 = H2O / (0.1 M CHaCOONH4) 90/10; B = CH3CN / (0.1M CH3COONH4) 90/10, A / B gradient: 90/10 to 22/78] for

give 84 mg (20%) of a yellow powder.

[MH] + = 1125

Step 1.8 2,2'-Oxybis [{ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4,1-diyl (2-methylmdolizma-1,3-] acid

diyl) carboml (2,4-dioxo-1,4-dihydroqumazolma-6,3 (2H) -diyl)]} diacetic

A molar solution of sodium hydroxide (0.15 mL; 0.15 mmol) is added to a solution of 2,2'-oxybis [{ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4.1 -diyl (2-methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline- 6.3 (2H) -diyl)]} methyl diacetate (107 mg; 0.10 mmol) in 4 mL of NMP. The solution is stirred at room temperature for 24 hours and then processed in a hydrochloric acid solution (0.1 M). The precipitate obtained is filtered off, washed with water and dried in vain to give 101 mg (97%) of a yellow-orange powder.

[MH] '= 1095

Step 1.9 Lysine acid salt 2,2 '- {oxibis [ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4,1-diyl (2-methylmdolizma-

1,3-diyl) carboml (2,4-dioxo-1,4-dihydroqumazolma-6,3 (2H) -diyl)]} diacetic

2,2'-Oxybis [{ethane-2,1-diyloxyethane-2,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1,4 - 25 dihydroquinazoline-6.3 (2H) -diyl)]} diacetic (101 mg; 0.09 mmol) is added to a lysine solution (27 mg; 0.14

mmol) in 3 mL of water. The solution is stirred for 4 h, filtered and lyophilized. The lyophilisate is taken up in diethylether and the suspension is stirred for 3 h, filtered and dried under vacuum to give 112 mg (2 lysine; 87%) of a yellow powder.

LCMS (method 1): [MH] '= 1095, RT = 7.21 min

1 H NMR [(CD3) 2SO, 400 MHz]: 6 ppm 9.42 (d, 2 H) 8.09 (d, 2 H) 7.87 (dd, 2 H) 7.43 (d, 2 H ) 7.30 (d, 2 H)

7.23 (d, 4 H) 7.14 (td, 2 H) 7.01 (d, 4 H) 6.91 (td, 2 H) 6.50-9.00 (br s, 8 H) 4.28 (s, 4 H) 4.11 (m, 4 H) 3.78 (m, 4 H) 3.55-3.64 (m, 8 H) 3.15 (t, 2 H) 2 , 72 (t, 4 H) 1.77 (s, 6 H) 1.28-1.73 (m, 12 H)

Example 2: 2,2 '- {Hexane-1,6-diylbis [immo (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylmdolizma-1,3-diyl) carboml ( 2,4-dioxo-1,4-dihydroqumazolma-6.3 (2H) -diyl)]} diacetic (compound No. 4)

Step 2.1 [6 - ({1 - [4- (2-ferc.-butoxy-2-oxoethoxy) feml] -2-methylmdolizm-3-yl} carboml) -2,4-dioxo-1,4-

dihydroquinazolin-3 (2H) yl] methyl acetate

{6 - [(1-Bromo-2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} methyl acetate [described in Step 1.5.] (0.85 g; 1.81 mmol), [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] tert-butyl acetate [CAS 769968- 17-4; D. Fan et al, Journal of Organic Chemistry, 2007, 72 (14), 5350-5357] (0.91 g; 2.71 mmol), 5.4 mL of 40 a molar solution of potassium phosphate, 17 mL of 1,2-dimethoxyethane and the PdCh catalyst (dppf) (198 mg; 0.27 mmol) are successively introduced into a reactor, under argon. The mixture is heated at reflux for 2 hours under argon. The reaction medium is filtered through Celite. The filtrate is diluted with ethyl acetate and the solution is washed with a saturated solution of potassium hydrogen carbonate and with a saturated solution of sodium chloride, and then dried over sodium sulfate and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM / EtOH: 100/0 to 80/10). 0.46 g (42%) of a

yellow-red powder.

[M + H] + = 598

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Step 2.2 Acid [4- (3 - {[3- (2-methoxy-2-oxoethyl) -2,4-dioxo-1,2,3,4-tetrahydroqumazolm-6-yl] carboml} -2-

methylmdolizm-1-yl) phenoxy] acetic

Trifluoroacetic acid (1.2 mL, 15.4 mmol) is added to a solution of [6 - ({1- [4- (2-ferc.-butoxy-2-oxoethoxy) phenyl] -2- methylindolizin-3- il} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) yl] methyl acetate (0.46 g; 0.77 mmol) in 4 mL dichloromethane. The solution is stirred at room temperature for 4 h and then concentrated to dryness. The residue obtained is taken up in 5 mL of W, W-dimethylformamide and processed in a saturated aqueous solution of sodium hydrogen carbonate. The solution is washed with a mixture of THF / EtOAc, then neutralized to pH 7 by adding a molar solution of clorldric acid. The precipitate formed is filtered and dried in vacuo to give 0.36 g (87%) of a yellow powder.

[M + H] + = 542

Step 2.3 2,2 '- {hexane-1,6-diylbis [immo (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylmdolizma-1,3-

diyl) carboml (2,4-dioxo-1,4-dihydroqumazolma-6.3 (2H) -diyl)]} methyl diacetate

Triethylamine (100 pl; 0.68 mmol), PyBOP (221 mg; 0.43 mmol) and hexane-1,6-diamine (20 pl; 0.17 mmol) are added successively to an acid solution [4- ( 3 - {[3- (2-Methoxy-2-oxoethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6- yl] carbonyl} -2-methylindolizin-1-yl) phenoxy] acetic (184 mg; 0.34 mmol) in 3 mL of NMP at 0 ° C under nitrogen. The reaction mixture is stirred at room temperature for 17 h and then poured into a mixture of ethyl acetate / THF. The organic solution is washed with a 0.1 M solution of hydrochloric acid, with a saturated solution of sodium hydrogen carbonate and with a saturated solution of sodium chloride, and then dried over sodium sulfate and concentrated to dryness. give a brown paste that is used in the next stage of saponification.

[M + H] + = 165

Step 2.4 Acid 2,2 '- {hexane-1,6-diylbis [immo (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylmdolizma-1,3-diyl) carbomlo (2 , 4-dioxo-1,4-dihydroqumazolma-6,3 (2H) -diyl)]} diacetic

Obtained according to the process described in Step 1.8, using 2,2 '- {hexane-1,6-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylindolizine) -1,3-diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-6.3 (2H) -diyl)]} methyl diacetate, in the form of a yellow powder (32% for the 2 stages) .

[MH] '= 1133

Step 2.5 Sodium acid salt 2,2 '- {hexane-1,6-diylbis [immo (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2- methylmdolizma-1,3-diyl) carboml (2,4-dioxo-1,4-dihydroqumazolma-6,3 (2H) -diyl)]} diacetic

2,2 '- {Hexane-1,6-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl acid (2,4 - Diacetic dioxo-1,4-dihydroquinazoline-6.3 (2H) -diyl)]} is added to a solution of sodium hydroxide (1 M, 70 pl; 0.07 mmol) diluted in 20 mL of water. The solution is stirred at room temperature and then lyophilized. The lyophilisate is taken up in diisopropylether, filtered and dried in vacuo to give 29 mg (sodium salt; 84%) of a yellow powder.

LCMS (method 1): [MH] '= 1133; RT = 6.90 min

1 H NMR [(CDa) 2SO, 400 MHz]: 6 ppm 9.45 (d, 2 H) 8.15 (d, 2 H) 8.12 (t, 2 H) 7.91 (dd, 2 H) 7.48 (d, 2 H) 7.32 (d, 6 H) 7.21 (td, 2 H) 7.05 (d, 4 H) 6.96 (td, 2 H) 4.49 (s , 4 H) 4.21 (s, 4H) 3.06-3.16 (m, 6H) 2.62-2.70 (m, 4H) 1.84 (s, 6 H) 1.17-1 , 76 (m, 20 H)

Example 3: Sodium salt of 2,2 '- ({[2- (2-hydroxyethoxy) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2- methylindolizine-1,3-] acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]) diacetic (compound No. 8)

Stage 3.1 N - ({2-ammo-5 - [(1-bromo-2-methylmdolizm-3-yl) carboml] feml} carboml) tert-butyl glycinate

Obtained according to the process described in Step 1.5, using 2-amino-5 - [(1-bromo-2-methylindolizin-3-yl) carbonyl] benzoic acid and glycine ferc.-butyl ester, in the form of a yellow powder (74%).

[M + H] + = 486.0

Step 3.2 {7 - [(1-bromo-2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} tert-butyl acetate

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Obtained according to the process described in Step 1.6, using W - ({2-amino-5 - [(1-bromo-2-methylindolizin-3- yl) carbonyl] phenyl} carbonyl) ferc.-butyl glycinate in form of a yellow powder (52%).

[M + H] + = 511.9

Stage 3.3 [7 - {[1- (4-hydroxifeml) -2-methylmdolizm-3-yl] carboml} -2,4-dioxo-1,4-dihydroqumazolm-3 (2H) il] ferc.-butyl acetate

(4-Hydroxyphenyl) boronic acid (404 mg, 2.93 mmol), 3 mL of a 2M solution of potassium phosphate (5.86 mmol) and the PdCh (dppf) catalyst (206 mg, 0.29 mmol ) are added to a solution of {7 - [(1-bromo-2-methylindolizin-3- yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} ferc acetate. -butyl (1 g, 1.95 mmol) in 20 mL of DMF are placed in a microwave reactor under nitrogen. The reactor is closed tightly and the solution is heated for 30 min at 120 ° C in a microwave. The reaction medium is processed in water and extracted with EtOAc. The organic phase is washed with a saturated aqueous solution of NaCl, dried over Na2SO4, and concentrated to dryness. The oil obtained is purified by flash chromatography on silica (DCM / EtOH: 100/0 to 90/10] to give 888 mg (86%) of a yellow solid.

[M + H] + = 526.0

Step 3.4 {7 - [(1- {4 - [(5-chloropentyl) oxy] phenyl} -2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) il} ferc.-butyl acetate

Sodium hydride (60% oil suspension, 332 mg, 7.61 mmol) is added to a solution of [7 - {[1- (4- hydroxyphenyl) -2-methylindolizin-3-yl] carbonyl} -2 , 4-dioxo-1,4-dihydroquinazolin-3 (2H) yl] ferc.-butyl acetate (2 g, 3.81 mmol) in solution in 38 mL of DMF at -5 ° C. After 15 min of stirring at -5 ° C, 1-chloro-5-iodopentane (0.53 mL, 3.81 mmol) is added. The reaction mixture is stirred for 3 h at -5 ° C, cooled to room temperature and processed in a molar solution of KHSO4. The yellow precipitate obtained is filtered off and then purified by flash chromatography on silica (DCM / EtOH: 100/0 to 90/10) to give 2.11 g (yield: 88%) of a yellow solid.

[M + H] + = 629.2

Step 3.5 {7 - [(1- {4 - [(5-iodopentyl) oxy] phenyl} -2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) il} ferc.-butyl acetate

A mixture of {7 - [(1- {4 - [(5-chloropentyl) oxy] phenyl} -2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H ) il} ferc.-butyl acetate (4.0 g, 6.35 mmol) and potassium iodide (10.53 g, 63.48 mmol) in 63 mL of DMF is stirred at 80 ° C for 6 h. It is cooled to room temperature and processed in a molar solution of KHSO4. The yellow precipitate obtained is filtered off and then washed with water and dried in a vacuum to give 3.96 g (yield: 86%) of a yellow solid.

[M + H] + = 722.3

Step 3.6 {7 - [(1- {4 - [(5 - {[2- (2-hydroxyethoxy) ethyl] amino} pentyl) oxy] phenyl} -2-methylindolizin-3-yl) carbonyl] -2.4 -dioxo-

1,4-dihydroquinazolm-3 (2H) -yl} ferc.-butyl acetate

Potassium carbonate (0.48 g, 3.46 mmol) and {7 - [(1- {4 - [(5-iodopentyl) oxy] phenyl} -2-methylindolizin-3-yl) carbonyl] -2.4 -dioxo-

1.4-dihydroquinazolin-3 (2H) yl} ferc.-butyl acetate (0.50 g, 0.69 mmol) are added to a solution of 2- (2- aminoethoxy) ethanol (0.73 g, 6.93 mmol) in 7 mL of DMF. The solution is stirred for 24 h at room temperature and then processed in a molar solution of KHSO4. The precipitate formed is filtered off, washed with water and dried in a vacuum to give 380 mg (yield: 79%) of a brown powder.

[M + H] + = 699.3

Step 3.7 2,2 '- ({[2- (2-hydroxyethoxy) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carboml (2 , 4-dioxo-1,4-dihydroqumazolma-7.3 (2H) -diyl)]) ferc.-butyl diacetate

{7 - [(1- {4 - [(5-iodopentyl) oxy] phenyl} -2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl } Ferc.-Butyl acetate (0.54 g, 0.75 mmol) is added to a mixture of {7 - [(1- {4 - [(5 - {[2- (2-hydroxyethoxy) ethyl) amino] amino } pentyl) oxy] phenyl} -2-methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} ferc.-butyl acetaium (0.35 g, 0.50 mmol) and potassium carbonate (104 mg, 0.75 mmol) in 5 mL of DMF. The reaction mixture is stirred for 24 h at room temperature and then processed in a molar solution of KHSO4. The precipitate formed is filtered off, washed with water and dried in a vacuum to give 588 mg (yield: 90%) of a brown powder.

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[M + H] + = 1291.4

Step 3.8 2,2 '- ({[2- (2-Hydroxyethoxy) ethyl] immo} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylmdolizma-1,3-diyl) carboml ( 2,4-dioxo-1,4-dihydroqumazolma-7.3 (2H) -diyl)]) diacetic

Trifluoroacetic acid (0.44 g, 3.89 mmol) is added to 2,2 '- ({[2- (2-hydroxyethoxy) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-Methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2W) -diyl)]) diacetate

ferc.-butyl (0.50 g, 0.39 mmol) suspended in 4 mL of a mixture of DCM / MeOH (1/1). The solution is stirred for 8 h at room temperature. The reaction mixture is processed in water. The precipitate formed is filtered off, washed with water and then with ethanol, and dried under vacuum. Purification by preparative HPLC on Kromasil C18 10 pm reverse phase [A = H2O / (0.1M CH3Co0nH4) 90/10; B = CHaCN / (0.1 M CHaCOONH4) 90/10, A / B gradient: 70/30 to 56/44] gives 25 mg (5%) of a yellow powder.

[M + H] + = 1180.2

Step 3.9 Sodium salt of the acid 2,2 '- ({[2- (2-hydroxyethoxy) ethyl] immo} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2- methylmdolizma-1,3-diyl) ) carboml (2,4-dioxo-1,4-dihydroqumazolma-7.3 (2H) -diyl)]) diacetic

Obtained according to the process described in Step 2.5, using 2,2 '- ({[2- (2- hydroxyethoxy) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2 -methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]) diacetic (25 mg, 0.02 mmol), as a solid yellow.

LCMS (method 1): [M + H] + = 1180, RT = 7.36 min

1 H NMR [(CD3) 2SO, 500 MHz]: 6 ppm 9.20 (br s, 2 H) 8.09 (d, 2 H) 7.69 (br s, 2 H) 7.44 (d, 2 H) 7.31 (d, 4 H) 7.04-7.11 (td, 2 H) 7.02 (d, 4 H) 6.85 (td, 2 H) 4.65 (br s, 1 H) 4.13 (s, 4 H) 4.00 (t, 4 H) 3.46 (t, 4 H) 3.40 (t, 2 H) 2.56 (t, 2 H) 2.43 (t, 4 H) 1.94 (s, 6 H) 1.75 (m, 4 H) 1.39-1.50 (m, 8 H)

Example 4: Acid [7 - ({1- [4 - ({9- [4- (3 - {[3- (carboxymethyl) -2,4-dioxo-1,4-dihydroqumazolm-7 (2W) -yl) ] carboml} -2- methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5 phosfanon-1-yl} carbamoyl) phenyl] -2 -

methylmdolizm-3-yl} carboml) -2,4-dioxo-1,4-dihydroqumazolm-3 (2H) -yl] acetic acid (compound No. 16).

Stage 4.1 4- (3 - {[3- (2-ferc.-butoxy-2-oxoethyl) -2,4-dioxo-1,2,3,4-tetrahydroqumazolm-7-yl] carboml} -2-

Methylindolizin-1-yl) benzyl benzoate

{4 - [(benzyloxy) carbonyl] phenyl} boronic acid (0.7 g, 2.73 mmol), 5.5 mL of a molar solution of potassium phosphate and the catalyst of PdCh (dppf) (192 mg, 0 , 27 mmol) are added to a solution of {7 - [(1-bromo-2-methylindolizin-3- yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} acetate of ferc.-butyl [described in Step 3.2] (1 g, 1.82 mmol) in 20 mL of DMF is placed in a microwave reactor under nitrogen. The reactor is closed tightly and the solution is heated for 30 min at 80 ° C in a microwave. The reaction medium is cooled and processed in a molar solution of KHSO4, and extracted with EtOAc. The organic phase is washed with a saturated aqueous solution of NaCl, dried over Na2SO4, and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM / EtOH: 100/0 to 80/20] to give 1.08 mg (92%) of a yellow solid.

[M + H] + = 644.2

Stage 4.2 4- (3 - {[3- (2-Ferc.-Butoxy-2-oxoethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl] carbonyl} -2- methylindolizin- 1-yl) benzoic

Palladium on carbon (10% active, 0.2 g) and 4- (3 - {[3- (2-ferc.-butoxy-2-oxoethyl) -2,4-dioxo-1,2,3,4 - Benzyl tetrahydroquinazolin-7-yl] carbonyl} -2-methylindolizin-1-yl) benzoate (1 g, 1.55 mmol) is added, under nitrogen, to ammonium formate (0.97 g, 15.54 mmol ) in solution in 15 mL of DMF. The reaction mixture is stirred for 3 h at room temperature and filtered through Celite, and the filtrate is concentrated to dryness. The solid obtained is collected in diisopropylether. After filtration and drying in vacuum, 732 mg (yield: 85%) of a green solid are obtained.

[M + H] + = 554.1

Stage 4.3 [7 - ({1- [4 - ({9- [4- (3 - {[3- (2-ferc.-butoxy-2-oxoethyl)) -2,4-dioxo-1,4-dihydroqumazolm-7 (2W) -il] carboml} -2- methylmdolizm-1-yl) feml] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5-phosfanon-1-yl} carbamoyl) phenyl] -2-methylindolizin-3-yl} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl] ferc.-butyl acetate

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Triethylamine (0.25 mL, 1.81 mmol) and HBTU (0.16 g, 0.40 mmol) are added to a solution of acid 4- (3 - {[3- (2-ferc.- butoxy-2 -oxoethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl] carbonyl} -2-methylindolizin-1-yl) benzoic acid (0.2 g, 0.36 mmol) in 10 mL DMF at 0 ° C. After stirring for 15 min hydrogen bis (2-aminoethanol) phosphate (0.046 g, 0.18 mmol) is added. The reaction mixture is stirred for 24 h at room temperature and then processed in water. The precipitate formed is filtered off and dried in vacuo to give 156 mg (yield: 34%) of a yellow solid.

[M + H] + = 1255.2

Stage 4.4 Acid [7 - ({1- [4 - ({9- [4- (3 - {[3- (carboxymethyl) -2,4-dioxo-1,4-dihydroqumazolm-7 (2W) -yl] carboml}) -2-

methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5-phosfanon-1-yl} carbamoyl) phenyl] -3-yl-2- methylmdolizm} carboml) -2,4-dioxo-1,4-dihydroqumazolm-3 (2H) -yl] acetic

Obtained according to the process described in Step 3.7, using [7 - ({1- [4 - ({9- [4- (3 - {[3- (2-ferc.-butoxy-2- oxoethyl)) - 2 4-dioxo-1,4-dihydroquinazolin-7 (2H) -yl] carbonyl} -2-methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa- 8-aza-4A-phosfanon-1-yl} carbamoyl) phenyl] -2-methylindolizin-3-yl} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl] ferc acetate .-Butyl, and after purification by preparative HPLC on Kromasil C18 10 pm reverse phase [A = H2O / (0.1 M CHaCOONH4) 90/10; B = CH3CN / (0.1M CH3COONH4) 90/10, gradient A / B 70/30 to 95/5], in the form of a yellow powder (yield = 3%).

[M + H] + = 1143.2

Stage 4.5 Sodium acid salt [7 - ({1- [4 - ({9- [4- (3 - {[3- (carboxymethyl)) -2,4-dioxo-1,4-dihydroqumazolm-7 (2H) -yl ] carbonyl} -2-methylindolizin-1-yl) feml] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5-phosfanon-1- yl} carbamoyl) feml] - 2-methylmdolizm-3-yl} carboml) -2,4-dioxo-1,4-dihydroqumazolm-3 (2H) -yl] acetic acid

Obtained according to the process described in Step 2.5, using acid [7 - ({1- [4 - ({9- [4- (3 - {[3- (carboxymethyl)) -

2,4-dioxo-1,4-dihydroquinazolin-7 (2H) -yl] carbonyl} -2-methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8 -aza-

4A5-phosfanon-1-yl} carbamoyl) phenyl] -3-yl-2-methylindolizin} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl] acetic acid

form of a yellow solid (yield: 75%)

LCMS (method 2): [M + H] + = 1143, RT = 9.98 min

1 H NMR [(CD3) 2SO, 500 MHz]: 6 ppm 11.87 (br s, 2 H) 9.77 (t, 2 H) 9.41 (d, 2 H) 8.15 (d, 2 H ) 8.04 (d, 4 H) 7.89 (dd, 2 H) 7.52 (d, 2 H) 7.42 (d, 4 H) 7.32 (d, 2 H) 7.20 ( td, 2 H) 6.97 (td, 2 H) 4.24 (s, 4 H) 3.89-3.96 (m, 4 H) 3.42 (c, 4 H) 1.84 (s , 6 H)

Example 5: Sodium salt of 2,2 '- {ethane-1,2-diylbis [immo (2-oxoethane-2,1-diyl) oxybenzene-3,1- acid

diylcarbomlimm (2-methylmdolizma-1,3-diyl) carbomlo (2,4-dioxo-1,4-dihydroqumazolma-7,3 (2H) -diyl)]} diacetic

(compound No. 21)

Stage 5.1 [7- {1 - [(difemlmethylidene) ammo] -2-methylmdolizm-3-yl} carboml) -2,4-dioxo-1,4-dihydroqumazolm-3 (2ft) -yl] tert-butyl acetate

Cesium carbonate (0.51 g, 1.59 mmol), Xantphos (0.98 g, 1.70 mmol), palladium acetate (0.19 g, 0.85 mmol) and benzophenone-imine (2.85 mL, 17.0 mmol) are added to a solution of {6 - [(1-bromo-2-methylindolizin-3-yl) carbonyl] -

2.4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} methyl acetate [described in Step 1.5.] (2.0 g, 4.25 mmol) in 90 mL of DMF under argon. The reaction medium is stirred under argon at 100 ° C for 2 days. After cooling, the reaction medium is diluted with ethyl acetate, and the solution is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The oil obtained is purified by flash chromatography on silica (toluene / EtOAc: 100/0 to 50/50] to give 1.33 g of a red powder.

[MH] + = 571.2

Stage 5.2 {7 - [(1-ammo-2-methylmdolizm-3-yl) carboml] -2,4-dioxo-1,4-dihydroqumazolm-3 (2ft} -yl} methyl acetate hydrochloride

0.53 mL of a 4 M solution of clorldric acid in anhydrous dioxane is added to a solution of [7- {1- [(diphenylmethylidene) amino] -2-methylindolizin-3-yl} carbonyl) -2,4-dioxo -1,4-dihydroquinazolin-3 (2H) -yl] tert-butyl acetate (1.3 g, 1.34 mmol) in 7 mL of a mixture of DCM / MeOH (5/1). After 24 h of stirring at room temperature, the precipitate formed is filtered off, washed with DCM and dried in a vacuum at 40 ° C to give 0.4 g (hydrochloride; 67%) of a yellow powder.

[MH] + = 407.1

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Step 5.3 2,2 '- {ethane-1,2-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-3,1-diylcarbonylimino (2-methylindolizine-1,3-diyl) carboml (2, 4-dioxo-1,4-dihydroqumazolma-7.3 (2H) -diyl)]} methyl diacetate

Triethylamine (0.23 mL, 1.63 mmol) and HBTU (285 mg, 0.75 mmol) are added to a suspension of 3,3 '- {ethane-1,2-diylbis [imino (2-oxoethane-) acid 2,1-diyl) oxy]} dibenzoic [CAS 944446-34-8; WO 2007080325] (136 mg, 0.33 mmol) in 5 mL of DMF at 0 ° C. After stirring for 30 min, {7 - [(1-amino-2- methylindolizin-3-yl) carbonyl] -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) -yl} hydrochloride is added methyl acetate (318 mg, 0.72 mmol). The solution is stirred for 10 h at room temperature and then processed in a saturated aqueous solution of sodium hydrogen carbonate. The precipitate is filtered off and washed with water and then dried in a vacuum to give 370 mg (yield: 94%) of a green solid.

[MH] + = 1193.3

Step 5.4 Acid 2,2 '- {ethane-1,2-diylbis [immo (2-oxoethane-2,1-diyl) oxybenzene-3,1-diylcarbomlimm (2-

methylmdolizma-1,3-diyl) carboml (2,4-dioxo-1,4-dihydroqumazolma-7.3 (2H) -diyl)]} diacetic

Obtained according to the process described in Step 1.8, using 2,2 '- {ethane-1,2-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-3,1-diylcarbonylimino (2-methylindolizine) -1,3-diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) - diyl)]} methyl diacetate, and after purification by preparative HPLC on Kromasil C18 10 pm of reverse phase [A = H2O / (CH3COONH 0.1 M) 90/10; B = CH3CN / (0.1 M CH3COONH4) 90/10, A / B gradient: 95/5 to 69/31], in the form of a yellow powder (yield = 59%).

[MH] + = 1165.1

Step 5.5 Sodium salt of acid 2,2 '- {ethane-1,2-diylbis [immo (2-oxoethane-2,1-diyl) oxybenzene-3,1-

diylcarbomlimm (2-methylmdolizma-1,3-diyl) carbomlo (2,4-dioxo-1,4-dihydroqumazolma-7,3 (2H) -diyl)]} diacetic

Obtained according to the process described in Step 2.5, using 2,2 '- {ethane-1,2-diylbis [imino (2- oxoethane-2,1-diyl) oxybenzene-3,1-diylcarbonylimino (2- Methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline- 7,3 (2H) -diyl)]} diacetic, in the form of a yellow solid (yield: 70%).

LCMS (method 2): [M + H] + = 1165, RT = 5.95 min

1 H NMR [(CD3) 2SO, 500 MHz]: 6 ppm 10.23 (br s, 2 H) 9.44 (br s, 2 H) 8.44 (br s, 2 H) 8.08 (d, 2 H) 7.81 (br s, 2 H) 7.64-7.70 (m, 4 H) 7.47 (d, 2 H) 7.42 (t, 2 H) 7.20 (td, 2 H) 7.17 (br. S, 2 H) 7.15 (dd, 2 H) 6.95 (td, 2 H) 4.53 (s, 4 H) 4.12 (s, 4 H) 3.20-3.24 (m, 4 H) 1.81 (s, 6 H)

The following table illustrates the chemical structures and physical properties of some examples of compounds according to the invention. In this table:

- in the column "salt", "Lys" and "Na" represent, respectively, a compound in the form of salt of D, L-lysine or sodium salt, and the relationship between parentheses is the ratio (base: diacid),

- Ph represents a phenyl group,

- the RT column indicates the retention time of the compound, and

- LCMS features, as described below, indicate successively the high resolution liquid chromatographic analytical method used and detailed below (method 1 or 2), the peak [MH] - or [M + H] + is identified by mass spectrometry and the retention time of the compound, expressed in minutes.

* Method 1

Instrument: HPLC system type 1100 (Agilent); single quadrupole mass spectrometer of type MSD (Agilent)

Column: Waters X Terra C18 3.5 pm (2.1 x 50 mm)

Solvent A: H2O + ACONH410 mM pH 7; Solvent B: CH3CN Flow rate: 0.4 mL / min

Gradient: t = 0 min 0% of B; t 10 min 90% B; t 15min 90% B Detection: UV 220 nm

lonizacion: electroprojection positive mode ESI + or ESI-

* Method 2: see method 1 with gradient change Gradient: t = 0 min 0% of B; t 30 min 90% B; t 35 min 90% of B

Table of examples

 M1-L-M2

 M having the general formula as follows:

 / r R RWN N-R yjry ^ R <0 0 (M)

 N °

 R1 R2 R3 R4 L Salt [M-H] - [M + H] + RT (min) LCMS method

 one

 -Ph-4-O * CH3 H CH2COO H * (CH2) 2 [O (CH2) 2] 2O (CH2) 2 * NJ '(/) 1095 / 7.21

 one

 2

 -Ph-3-O * CH3 H CH2COO H * (CH2) 2 [O (CH2) 2] 2O (CH2) 2 * NJ 1095 / 7.28 1

 3

 -Ph-4-O * CH3 H CH2COO H * (CH2) 2O (CH2) 2O (CH2) 2 * Lys (3) 1051 / 7.28 1

 4

 -Ph-4-O * CH3 H CH2COO H * CH2CONH (CH2) aNHCOCH2 * NJ '(/) 1133 / 6.90 1

 5

 -Ph-4-O * CH3 H CH2COO H * CH2CONH (CH2) 4NHCOCH2 * Na (2) 1105 / 6.56 1

 6

 -Ph-3-O * CH3 H CH2COO H * CH2CONH (CH2) aNHCOCH2 * Na (2) 1133 / 6.91 1

 7

 -Ph-3-O * CH3 H CH2COO H * CH2CONH (CH2) 4NHCOCH2 * Na (2) 1105 / 6.65 1

 8

 -Ph-4-O * CH3 H CH2COO H * (CH2) 5N [(CH2) 2O (CH2) 2OH] (CH2) 5 * Na (2) / 1180 7.36 1

 9

 -Ph-4-O * CH3 H CH2COO H * (CH2) 5N [CH2CH3] (CH2) 5 * Na (2) / 1120 7.50 1

 10

 -Ph-4-O * - H CH2COO * (CH2) 5N [(CH2) 2 ^ -morpholine] (CH2) 5 * Na / 1205 15.66 2

 CH3 H (2)

 eleven

 -Ph-4-O * CH3 H CH2COO H * (CH2) 5N [(CH2) 2N-N- methylpiperazine)] (CH2) 5 * Na (2) / 1218 15.41 2

 12

 -Ph-4-O * CH3 H CH2COO H * (CH2) 5N [(CH2) -pyridin-4-yl] (CH2) 5 * Na (2) / 1183 7.53 1

 13

 -Ph-4-O * CH3 H CH2COO H * (CH2) 5N {(CH2) - [4- N (CH3) 2Ph]} (CH2) 5 * Na (2) / 1225 17.89 2

 14

 -Ph-4-O * CH3 H CH2COO H * (CH2) 5N [(CH2) 2N (CH2CH3) 2] (CH2) 5 * Na (2) / 1191 8.18 1

 fifteen

 -Ph-4-O * CH3 H CH2COO H * (CH2) 3N [(CH2) 2] 2N (CH2) 3 * HCl (2) / 1105 7.32 1

 16

 -Ph-4- CONH * CH3 H CH2COO H * (CH2) 2OP (O) (OH) O (CH2) 2 * Na (3) / 1147 9.98 2

 17

 -Ph-4- CONH * CH3 H CH2COO H * (CH2) 2O (CH2) 2O (CH2) 2 * Na (2) / 1107 11.84 2

 18

 -Ph-3- CONH * CH3 H CH2COO H * (CH2) 2O (CH2) 2O (CH2) 2 * Na (2) / 1107 6.29 1

 19

 -Ph-3- CONH * CH3 H CH2COO H * (CH2) 2OP (O) (OH) O (CH2) 2 * Na (3) / 1143 5.67 1

 twenty

 NHCOP h-3-O * CH3 H CH2COO H * CH2CONH (CH2) 2NHCOCH2 * Na (2) / 1165 5.95 1

The results of in vitro and in vivo pharmacological tests carried out in order to determine the properties of the compounds of the invention are listed below:

5

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fifteen

twenty

25

30

 Compound

 Activation% with respect to FGF2 (in vitro) CE50

 2

 44% EC50 <1 nM

 3

 74% EC50 <1 nM

 4

 57% EC50 <1 nM

 5

 30% EC50 <100n M

 6

 29% EC50 <100n M

 7

 28% EC50 <100n M

 8

 42% EC50 <1 nM

 9

 28% EC50 <100n M

 10

 41% EC50 <1 nM

 eleven

 63% EC50 <1 nM

 12

 42% EC50 <1 nM

 13

 23% EC50 <100n M

 14

 62% EC50 <1 nM

 fifteen

 24% EC50 <100n M

 16

 82% EC50 <1 nM

 17

 44% EC50 = 10 nM

 18

 85% EC50 <1 nM

 19

 35% EC50 = 3 nM

 twenty

 61% EC50 <3 nM

In vitro angiogenesis model

The products were tested for their ability to cause reorganization of human venous endothelial cells (HUVECs) in matrigel (Becton Dickinson 356230) diluted in collagen (rat tail collagen, type I: Becton Dickinson 354236). After 24 hours, the cells are observed under a microscope with an X4 objective and the length of the pseudotubules is measured by means of an image analyzer (BIOCOM-logiciel Visiolab 2000).

For the in vitro angiogenesis assay, the compounds of the invention demonstrated a specific activity between 10 "6 M and 10" 12 M. By way of example, compounds 3 and 16 are active at a concentration of 10 nM in the model of angiogenesis in vitro.

Sponge model of angiogenesis

The sponge model of angiogenesis is an adaptation of the technique of Andrade et al. [Andrade SP, Machado R., Teixeiras, Belo AV, Tarso AM, Beraldo WT - Sponge-induced angiogenesis in mice and the pharmacological reactivity of the neovasculature quantitated by fluorimetric method, Microvascular Research, 1997, 54: 253-61.]

The mice used are BalbC females from Charles River Laboratory, 7 to 10 weeks old. The animals are anesthetized by intraperitoneal injection of a mixture of xylazine / ketamine (1 mg / kg in each case in 0.9% NaCl). The animal's back is shaved and disinfected with hexomedin. A 5 mL subcutaneous air pocket is made in the animal's back with sterile air. An incision (approximately 1 cm) is then made in the upper part of the animal's back in order to implant the sponge in the pocket. The biocompatible cellulose sponge (Cellspon, Interchim, 10 mm in diameter) was previously sterilized (autoclave 20 min at 120 ° C) and impregnated with 50 µl of sterile solution containing the test product. The suture is made by inserting two 9 mm autoclip stainless steel clips (Subra). The wound is disinfected again with hexomedin. The animals are housed in individual cages throughout the duration of the experiment.

The test products are in solution in a mixture of 0.1% PBS / BSA: the recombinant human FGF2 (Peprotech) and the products of the invention are arranged in solution extemporaneously according to the selected concentration. In the two days following the implantation of the cellulose sponge, the test products in solution are directly reinjected into the implant through the skin of the animal, after having disinfected the area with hexomedin.

On the eighth day after implantation, mice are sacrificed with a lethal dose of sodium pentobarbital (CEVA sante animale, 10 mg / kg) administered intraperitoneally. The skin is cut around the sponge (approximately 1 cm) and the sponge is separated from the skin by removing the connective tissue. The sponge is cut into 3 or 4 pieces and placed in a tube containing ceramic beads with 1 mL of RIPA lysis buffer. Lysis

It is carried out by means of two stirring cycles for 20 seconds (FastPrep® FP 120). After freezing the supernatants at -20 ° C, the tubes are centrifuged at 8000 rpm for 10 minutes and the supernatants are removed in order to test hemoglobin.

To test hemoglobin, 50 µl of each sample is deposited in a 96-well plate, in duplicate. The range is prepared with human hemoglobin (ref H7379, Sigma®) in a solution of 4 mg / ml to 0.06 mg / ml in the RIPA lysis buffer. 50 ml of Drabkin reagent (Sigma®) are deposited in all wells (range + samples). The plate is incubated for 15 min at room temperature, in the dark. OD values are read on a spectrophotometer at 405 nm, using the Biolise software (Tecan, France). The Hb concentration in each of the samples is expressed in mg / mL according to the polynomial regression carried out using the 10 range.

By way of example, compound 4 is active at a concentration of 300 jM in the in vitro angiogenesis model.

The compounds of the invention exhibit an agonist activity of FGF receptors. They induce receptor dimerization and, by virtue of their low toxicity and their pharmacological and biological properties, the compounds of the present invention represent a therapy of choice in pathological conditions for which FGFs have a positive effect such as postvascular revascularization. ischemic, healing processes and neuronal, muscular and bone repair and regeneration processes.

One of the applications of the compounds of the invention is the treatment that requires an increase in angiogenesis such as post-ischemic treatment after peripheral artery occlusion or treatment of the consequences of cardiac ischemia. The compounds described in the invention can be used in the treatment of diseases associated with narrowing of the coronary arteries and, in particular, in the treatment of angina pectoris or thromboangeitis obliterans. In addition, the compounds of said invention could represent a treatment of choice for the compensation of a deficiency in angiogenesis in pre-eclanthic placentas. Through their anti-apoptotic activity in endothelial cells, the products of said invention could provide a treatment of choice in vascular improvement in patients suffering from vascular damage and, in particular, patients suffering from ARDS.

Through their agonist activities of FGF receptors and their abilities to induce angiogenesis and to activate the mesenchymal cells involved in the phases of healing, the compounds of said invention represent a therapy of choice for the treatment of healing, in particularly in elderly or diabetic patients. The compounds presented in the invention could represent a treatment of choice for muscle regeneration.

By virtue of the agonist activity of the FGF receptor, the compounds of said invention could represent a treatment of choice in the treatment of nociception, in the treatment of chronic pain and in the treatment of peripheral neuropathy, particularly in diabetic patients.

Through the agonist properties of FGF receptors, the compounds of said invention could represent a treatment of choice in bone repair after a fracture.

The compounds of said invention represent a therapy of choice in the improvement of bioartificial pancreas graft survival in diabetic patients and, more generally, in the improvement of graft revascularization and graft survival.

Through their agonist activity of the FGF receptor, the compounds of said invention could provide a treatment of choice for the repair and protection of the hair follicle and in the protection and regulation of hair growth.

According to another of its aspects, the compounds according to the invention are used for the treatment of diseases that require the activation of FGF receptors. An object of the present invention is more particularly the use of a compound as defined above, to prepare a medicament that is used in the treatment of cardiac ischemia, the treatment of diseases associated with narrowing or clogging of the arteries. or of arteritis, treatment of angina pectoris, treatment of thromboangeitis obliterans, treatment of atherosclerosis, treatment to inhibit post-angioplasty or post-endoarterectoiTHa restenosis, treatment of cure, treatment for muscle regeneration, the

5

10

fifteen

twenty

25

30

35

40

treatment for myoblast survival, treatment of sarcopenia, loss of functionality of smooth sphincter muscles, treatment of nociception and treatment of chronic pain, treatment of peripheral neuropathy, treatment to improve survival of bioartificial pancreas grafting in the diabetic patient, treatment to cause a decrease in cholesterol associated with a decrease in adiposity, treatment to improve graft revascularization and graft survival, treatment of retinal degeneration, treatment of pigmentary retinitis, treatment of osteoarthritis, treatment of pre-eclampsia, treatment of vascular lesions and acute respiratory distress smdrome, treatment of bone protection or treatment for the protection of the hair follicle.

According to another of its aspects, an object of the present invention is, therefore, the use of a compound as defined above, to prepare a medicament that is used in the treatment of diseases that require the activation of the receptor of FGF An object of the present invention is, more particularly, the use of a compound as defined above, to prepare a medicament that is used in the treatment of cardiac ischemia, the treatment of diseases associated with narrowing or obstruction of the arteries or arteritis, treatment of angina pectoris, treatment of thromboangeitis obliterans, treatment of atherosclerosis, treatment to inhibit post-angioplasty or post-endoarterectoirn restenosis, treatment of scarring, treatment for muscle regeneration, treatment for myoblast survival, treatment of sarcopenia, loss of functionality of smooth sphincter muscles, treatment of nociception and treatment of chronic pain, treatment of peripheral neuropathy, treatment to improve the survival of the bioartificial pancreas graft in the diabetic patient, the treatment p To cause a decrease in cholesterol associated with a decrease in adiposity, treatment to improve graft revascularization and graft survival, treatment of retinal degeneration, treatment of pigmentary retinitis, treatment of osteoarthritis, the treatment of pre-eclampsia, the treatment of vascular lesions and the acute respiratory distress syndrome, the treatment of bone protection or the treatment for the protection of the hair follicle.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, and also at least one pharmaceutically acceptable excipient.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients that are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals or humans for the prophylaxis or treatment of the above disorders or diseases.

Appropriate unit administration forms include oral forms, such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular and intranasal administration forms, inhalation administration forms, topical , transdermal, subcutaneous, intramuscular or intravenous, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according to the invention in tablet form may comprise the following constituents:

Compound according to the invention 50.0 mg

Mannitol

Croscarmellose sodium Corn starch Hydroxypropyl methylcellulose Magnesium stearate

223.75 mg

6.0 mg

15.0 mg 2.25 mg

3.0 mg

There may be particular cases in which the higher or lower doses are appropriate; such dosages do not depart from the scope of the invention. In accordance with usual practice, the appropriate dosage for each of the patients is determined by the physician according to the method of administration and the weight and response of said patient.

In accordance with another of its aspects, the present invention also relates to a method for treating and / or preventing the pathological conditions indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.

Claims (12)

5 10 fifteen twenty 25 1. FGF receptor agonist compounds corresponding to the general formula: M1-L-M2 in which M1 and M2, which may be identical or different, each represent, independently of one another, a monomer unit M and L represents a linker group that links Mi and M2 covalently, characterized in that said monomer unit corresponds to the general formula M that follows: image 1 in which, * indicates the link site between monomer unit M and linker L, - Ri represents . a group -NHCOPh, said phenyl being substituted with an oxygen atom, so that the oxygen atom is the site of linkage between the monomer unit and the linker L; This group can be designated -NHCOPhO *, or . an aryl group, in particular phenyl, or a heteroaryl group, said group being substituted with a group selected from a divalent oxygen atom such that the oxygen atom is the site of linkage between the monomer unit and the linker L, or an amide group -CONH * -, so that the nitrogen atom is the site of union between the monomer unit and the linker L, - R2 represents an alkyl group, - R3 represents a hydrogen atom or a linear, branched, cyclic or partially alkyl group dclico, - R4 represents a hydrogen atom or an alkyl group or -alkyl-COORs, R5 representing a hydrogen atom or an alkyl group, L is chosen from the radicals that have the following formulas: .O.J ^ or 2 or (TO) (B) <C> R2 ’ OR ° x ° m P OH R2 " Mr (D) 5 10 fifteen twenty 25 30 35 40 Four. Five image2 in which - * indicates the connection atom of L with the monomer unit M in the substituent R1, - n represents an integer from 0 to 5, - m represents an integer from 1 to 5, - r represents an integer from 1 to 6, - R2 'and R2 ", which may be identical or different, represent a linear alkyl radical having 1 to 5 carbon atoms, and which may optionally be linked to form a ring, - R6 represents a (C1-C4) alkyl group, optionally substituted with one or more substituents selected from: - an aryl or heteroaryl group, optionally substituted with a group selected from a hydroxyl, amine or NR6'R6 "group, with R6 'and R6" being chosen, which may be identical or different, from a hydrogen atom or an alkyl group ( Ci-C4) linear, branched or cyclic, - a heterocycloalkyl group comprising at least one heteroatom chosen from a nitrogen atom and an oxygen atom optionally substituted with a linear or branched alkyl group, - a NR6'R6 "group, with R6 'and R6 being chosen, which may be identical or different, between a hydrogen atom or a linear, branched or cyclic (C1-C4) alkyl group, - an O-C1-C4 alkyl group optionally substituted with a hydroxyl group, in the form of a base or a salt by addition with an acid. 2. FGF receptor agonist compounds according to claim 1, characterized in that Ri represents a group -NHCO-PhO *, -Ph-O * or Ph-CONH *, in the form of a base or a salt by addition with an acid or with a base. 3. FGF receptor agonist compounds according to one of claims 1 or 2, characterized in that R2 represents a methyl group, in the form of a base or a salt by addition with an acid or with a base. 4. FGF receptor agonist compounds according to any one of claims 1 to 3, characterized in that: R3 represents a hydrogen atom, R4 represents a group -alkyl-COORs, R5 representing a hydrogen atom or an alkyl group, in the form of a base or a salt by addition with an acid or with a base. 5. FGF receptor agonist compounds of general formula M1-L-M2 according to any one of claims 1 to 4, so that the monomer units M1 and M2 are identical. 6. FGF receptor agonist compounds corresponding to the general formula M1-L-M2 according to any one of the preceding claims, characterized in that they are chosen from the following compounds: - Compound 1: 2,2 '- {oxibis [ethane-2,1-diyloxyethane-2,1-diyloxybenzene-3,1-diyl (2-methylindolizine-1,3-) acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-6.3 (2H) -dyl)]} diacetic; - Compound 2: 2,2 '- {oxibis [ethane-2,1-diyloxyethane-2,1-diyloxybenzene-3,1-diyl (2-methylindolizine-1,3-) acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-6.3 (2H) -diyl)]} diacetic; - Compound 3: 2,2 '- {ethane-1,2-diylbis [oxethane-2,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl (2,4-dioxo) acid -1,4-dihydroquinazoline-6.3 (2H) -diyl)]} diacetic; - Compound 4: 2,2 '- {hexane-1,6-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylindolizine-1,3- acid) diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-6.3 (2H) -diyl)]} diacetic; - Compound 5: 2,2 '- {butane-1,4-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-4,1-diyl (2-methylindolizine-1,3-) acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-6.3 (2H) -diyl)]} diacetic; - Compound 6: 2,2 '- {hexane-1,6-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-3,1-diyl (2-methylindolizine-1,3-diyl) carbonyl acid 2,4-dioxo-1,4-dihydroquinazoline-6,3 (2H) -diyl)]} diacetic; - Compound 7: 2,2 '- {butane-1,4-diylbis [imino (2-oxoethane-2,1-diyl) oxybenzene-3,1-diyl (2-methylindolizine-1,3-) acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-6.3 (2H) -diyl)]} diacetic; - Compound 8: 2,2 '- ({[2- (2-hydroxyethoxy) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) acid carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]) diacetic; - Compound 9: 2,2 '- {(ethylimino) bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl (2,4-dioxo-1, 4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic; 5 10 fifteen twenty 25 30 - Compound 10: 2,2 '- ({[2- (morpholin-4-yl) ethyl] imino} bis [pentane-5,1-diyloxybenzene-4,1-diyl (2-methylindolizine-1,3-] acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]) diacetic; - Compound 11: 2,2 '- ({[2- (4-metN-piperazin-1-N) etN] imino} bis [pentane-5,1-diyloxybenzene-4,1-diN (2- methylindolizine-1,3-diN) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]) diacetic; - Compound 12: 2,2'- {[(pyridin-4-NmetN) imino] bis [pentane-5,1-diNoxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl (2 , 4 dioxo-1,4-dihydroquinazoline-7.3 (2H) -diyl)]} diacetic; - Compound 13: 2,2 '- ({[4- (dimetNamino) bencN] imino} bis [pentane-5,1-diNoxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl acid ( 2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN) j) diacetic; - Compound 14: 2,2 '- ({[2- (dietNamino) etN] imino} bis [pentane-5,1-diNoxybenzene-4,1-diyl (2-methylindolizine-1,3-diyl) carbonyl acid ( 2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]) diacetic; - Compound 15: 2,2 '- {piperazine-1,4-diNbis [propane-3,1-diNoxybenzene-4,1-diyl (2-methylindolizine-1,3-] acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]} diacetic; - Compound 16: acid [7 - ({1- [4 - ({9- [4- (3 - {[3- (carboxymethyl)) -2,4-dioxo-1,4-dihydroquinazolin-7 (2H) - N] carbonN} -2-methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5-phosfanon-1-yl} carbamoyl) phenyl] -2-methylindolizin-3- yl} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) yl] acetic acid; - Compound 17: 2,2 '- {ethane-1,2-diNbis [oxethane-2,1-diNcarbamoNbenzene-4,1-diyl (2-methylindolizine-1,3-] acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]} diacetic; - Compound 18: 2,2 '- {ethane-1,2-diNbis [oxethane-2,1-diNcarbamoNbenzene-3,1-diyl (2-methylindolizine-1,3-] acid diyl) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]} diacetic; - Compound 19: acid [7 - ({1- [3 - ({9- [3- (3 - {[3- (carboxymethyl)) -2,4-dioxo-1,4-dihydroquinazolin-7 (2H) - N] carbonN} -2-methylindolizin-1-yl) phenyl] -4-hydroxy-4-oxido-9-oxo-3,5-dioxa-8-aza-4A5-phosfanon-1-yl} carbamoyl) phenyl] -2-methylindolizin-3- yl} carbonyl) -2,4-dioxo-1,4-dihydroquinazolin-3 (2H) yl] acetic acid; - Compound 20: 2,2 '- {ethane-1,2-diylbis [imino (2-oxoethane-2,1-diN) oxybenzene-3,1-diylcarbonylimino (2- Methylindolizine-1,3-diN) carbonyl (2,4-dioxo-1,4-dihydroquinazoline-7.3 (2H) -diN)]} diacetic. 7. Method for preparing an agonist compound of FGF receptors according to any one of claims 1 to 6, characterized in that: - the compound of formula (IX) image3 wherein m represents an integer from 1 to 5, R2 represents an alkyl group, PG1 represents an alkyl group and LG represents a halogen atom or an activated hydroxyl group, reacts with an R6-NH2 amine in the presence of a base for give the formula number (XV) image4 R6 having the same meaning as in claim 6, or the amine of formula (XVI) 5 10 fifteen twenty 25 30 35 40 image5 when the R6-NH2 amine is present in excess, - the isolated amine (XVI) reacts with a stoichiometric amount of the compound of formula (IX) to give the formula (XV), - the esters of formula (XV) are saponified. A medicament, characterized in that it comprises an agonist compound of FGF receptors according to any one of claims 1 to 6, or a salt by adding this compound with a pharmaceutically acceptable acid or base. 9. An FGF receptor agonist compound according to any one of claims 1 to 6, for use as a medicament. 10. Pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt of this compound and also at least one pharmaceutically acceptable excipient. 11. Use of an agonist compound of FGF receptors according to any one of claims 1 to 6, to prepare a medicament for the treatment of the consequences of cardiac ischemia, the treatment of diseases associated with narrowing or obstruction of arteries or arteritis, treatment of angina pectoris, treatment of thromboangeitis obliterans, treatment of atherosclerosis, treatment to inhibit post-angioplasty or post-endoarterectomy restenosis, treatment of treatment, treatment for muscle regeneration, the treatment for myoblast survival, the treatment of sarcopenia, the loss of functionality of the smooth muscles of the sphincters, the treatment of nociception and the treatment of chronic pain, the treatment of peripheral neuropathy, the treatment to improve the survival of bioartificial pancreas grafting in diabetic patients, the treatment This is to cause a decrease in cholesterol associated with a decrease in adiposity, treatment to improve graft revascularization and graft survival, treatment of retinal degeneration, treatment of pigmentary retinitis, treatment of osteoarthritis , treatment of pre-eclampsia, treatment of vascular lesions and acute respiratory distress smdrome, treatment of bone protection or treatment for hair follicle protection and hair growth regulation. 12. FGF receptor agonist compound according to any one of claims 1 to 6, for use thereof in the treatment of the consequences of cardiac ischemia, the treatment of diseases associated with narrowing or obstruction of the arteries or of arteritis, treatment of angina pectoris, treatment of thromboangeitis obliterans, treatment of atherosclerosis, treatment to inhibit post-angioplasty or post-endoarterectomy restenosis, treatment of cure, treatment for regeneration muscle, treatment for myoblast survival, treatment of sarcopenia, loss of functionality of the smooth muscles of the sphincters, treatment of nociception and treatment of chronic pain, treatment of peripheral neuropathy, treatment for improve the survival of bioartificial pancreas grafting in diabetic patients, the treatment to cause a dism cholesterol induction associated with a decrease in adiposity, treatment to improve graft revascularization and graft survival, treatment of retinal degeneration, treatment of pigmentary retinitis, treatment of osteoarthritis, treatment of pre-eclampsia, treatment of vascular lesions and acute respiratory distress syndrome, bone protection treatment or treatment for hair follicle protection and hair growth regulation.